This document provides information on diabetic neuropathy including: 1. It defines diabetic neuropathy as the presence of peripheral nerve dysfunction symptoms and/or signs in people with diabetes after excluding other causes. 2. It lists risk factors for developing diabetic neuropathy such as poor glycemic control, alcohol use, hypertension, smoking, and longer duration of diabetes. 3. It describes the pathogenesis of diabetic neuropathy including increased aldose reductase activity and non-enzymatic glycation of proteins.

1. DR KOUSHIK KR MONDAL
PGT, DEPT. OF GENERAL MEDICINE
R G KAR MEDICAL COLLEGE

2. Definition
An internationally agreed simple definition of Diabetic neuropathy for clinical
practice is
“the presence of symptoms and/or signs of peripheral
nerve dysfunction in people with diabetes after the
exclusion of other causes”
Boulton AJ et al. Diabetic neuropathies: a statement by
the American Diabetes Association. Diabetes Care. 2005 Apr;28(4):956-62.

3. Risk factors for the development of diabetic
neuropathy
Modifiable Risk Factors
 Poor glycemic control (Elevated
HbA1c)
 Alcohol
 Hypertension
 Cigarette Smoking
 Hypertriglyceridemia
Non-modifiable Risk Factors
• Obesity
• Older age
• Male sex
• Height
• Family h/o neuropathic disease
• Longer duration of diabetes
• Aldose reductase gene
hyperactivity
1.Harati Y. Diabetic Neuropathies: Unanswered Questions. Neurol Clin 25 (2007) 303–317
2.Tesfaye S, Chaturvedi N, Eaton SE, et al. Vascular risk factors and
diabetic neuropathy. N Engl J Med 2005;352(4):341.

4. PATHOGENESIS
Increased aldose reductase activity.
Auto oxidation of glucose
Non enzymatic glycation of
protein(AGE)
Activation of protein kinase C
Oxidative stress
Reduced serum levels of nerve growth
factor
Nerve ischemia/hypoxia.

5. CLASSIFICATION
1)IMPAIRED GLUCOSE TOLERANCE AND
HYPERGLYCEMIC NEUROPATHY
2)GENERALIZED NEUROPATHIES:
-sensorimotor(most common)(DSPN)
-acute painful(insulin neuritis)
-autonomic

6. Contd………..
3)FOCAL AND MULTIFOCAL NEUROPATHIES:
-cranial
-thoracolumbar
-lumbosacral radiculoplexus
-focal limb
4)SUPERIMPOSED CIDP

7. Symptoms
-Numbness or feeling of walking in cotton
-Sharp shooting or stabbing pain(Ad fibre)
-Dull constant or boring pain.(C fibre)
-Tingling pins & needles
-Allodynia
-Autonomic dysfunction(resting
tachycardia,constipation,orthostatic hypotension etc)

8. SIGNS:
 Significant distal weakness is uncommon but EDB
weakness may be there(in DSPN).
 Ankle reflexes are absent .
 Sensory loss in a length related distribution with the
toes and feet being most affected.
 Loss or impairment of all sensory modalities with
vibration sense often the first to go.
.

10. Investigation
 NCV
 quantitative sensory tests (QST) for vibration,
tactile, thermal warming, and cooling thresholds
 quantitative autonomic function tests (QAFT)
revealing diminished heart rate variation with deep
breathing, Valsalva maneuver, and postural testing &
BP testing.

11. Screeing
Neuropathy symptom score could also be useful in
clinical practice.
 The Michigan Neuropathy Screening Instrument
(MNSI) is a 15-item questionnaire that can be
administered to patients as a screening tool for
neuropathy.
 nerve impairment score of the lower limbs (NIS-
LL).
 The modified Neuropathic Disability Score.> 6
high chance of foot ulcer.

12. THE MODIFIED NEUROPATHIC DISABILITY
SCORE.

13. Devices for clinical screening.
 Semmes-Weinstein monofilament
 Assesses pressure perception when gentle pressure is applied to the
handle sufficient to buckle the nylon filament.
 One that exerts 10 g pressure, is most commonly used
 Also referred as 5.07 monofilament .
 Graduated Rydel-Seiffer tuning fork
 Tactile circumferential discriminator
 Neuropen

15.  16–34% of patients with diabetes report painful
neuropathic symptoms and the prevalence is
greater in type 2 diabetes, women and South
Asians [Ziegler et al. 2009; Abbott et al. 2011].
 The symptoms of painful diabetic neuropathy
(PDN) can be debilitating and can cause sleep
disturbances, anxiety and interfere with physical
functioning [Galer et al. 2000].

16. Pathophysiology of
Neuropathic Pain
 Excitotoxicity(decrease disinhibited pain system)
 Sodium channels-ectopic impulse generation
 Ectopic discharge
 Deafferentation
 Central sensitization
 maintained by peripheral input
 become hyperresponsive (sensitized) to peripheral input
 Chemical excitation of nonnociceptors
 Ectopic transduction.

17. Physiology of Pain Perception
Injury
Descending
Pathway
Peripheral
Nerve
Dorsal
Root
Ganglion
C-Fiber
A-delta Fiber
Ascending
Pathways
Dorsal
Horn
Brain
Spinal Cord

18. • Glutamate
• Substance P
• Brandykinin
• Prostaglandins
Pain
Initiators
• Serotonin
• Endorphins
• Enkephalins
• Dynorphin
Pain
Inhibitors
The Neurochemicals of Pain

19. Types of painful neuropathies
Acute (< 6 months)
 Truncal neuropathy.
 cachectic neuropathy-Acute,
painful,wt.loss,poor control of
DM
 Insulin neuritis -Acute painful,
weight loss, good control of
DM
 Painful 3rd cranial nerve palsy.
 Easy to treat.
Chronic(> 6 months)
 Distal symmetrical painful
sensorimotor
polyneuropathy
 Entrapment neuropathies
 Difficult to treat.

20. Symptoms of Neuropathic Pain
Symptom Description (example)
Spontaneous symptoms
– Spontaneous pain1 Persistent burning, intermittent shock-like or
lancinating pain
– Dysesthesias2 Abnormal unpleasant sensations
e.g. shooting, lancinating, burning
– Parasthesias2 Abnormal, not unpleasant sensations e.g. tingling
Stimulus-evoked
symptoms
– Allodynia2 Painful response to a non-painful stimulus
e.g. warmth, pressure, stroking
– Hyperalgesia2 Heightened response to painful stimulus e.g.
pinprick, cold, heat
– Hyperpathia2 Delayed, explosive response to any painful stimulus
1.Baron. Clin J Pain. 2000;16:S12-S20.
2. Merskey H et al. (Eds) In: Classification of Chronic Pain:
Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 1994:209-212.

21. Evaluation
The diagnosis of PDN is primarily clinical, based on history
of neuropathic pain and confirmatory examination findings,
establishing deficits associated with neuropathy.
Although one might argue that confirming neuropathy
using tests which assess large fibre deficits (loss of sensation,
monofilament exam, reflexes) are not relevant to painful
symptoms which are driven principally by small fibre
damage. (Ad & C Fibre)
Recent guidance has clearly stipulated that QSTs should not
be used as standalone tests for the diagnosis of neuropathic
pain [Backonja et al. 2013].

22. Diabetic Neuropathy- Pain
Assessment Scales

24.  Due to the subjective nature of the symptoms reported
by patients, these scales may not produce consistent
results and may lack the sensitivity to track any
objective changes in neuropathy status.
 Skin biopsies which measure intraepidermal nerve
fibre density have been used to diagnose and assess
neuropathy [Bakkers et al. 2014]
 Corneal confocal microscopy has been proposed as
a reliable, noninvasive marker of neuropathy that may
be used to objectively assess neuropathy in PDN [Shy
et al. 2003]

25.  Loss of cutaneous nerve fibers that stain positive for the neuronal antigen
protein gene product 9.5 in sensoryneuropathy. A, Normal epidermal fibers
in the back. B, Slightly reduced density and swelling in the proximal
thigh. C, Complete clearance in calf. (From McArthur JC, Stocks EA, Hauer P.
Epidermal nerve fiber density: normative reference range and diagnostic
efficiency. Arch Neurol 1998;55:1513-1520.)

27. Goals of Pain Management
Treat/prevent recurrence of pain-causing condition
Reduce pain
Improve physical/psychologic function
Improve quality of life

28. 1.Control of hyperglycemia.
 Open-label uncontrolled studies suggested near normoglycmia
helpful in painful neuropathic symptoms.
 Stability of glycemic control equally important to level of
achieved control.
 Lack of appropriately designed controlled studies
 Generally accepted that intensive diabetes therapy aimed at
near normoglycemia should be first step in the treatment of any
form of DN.
 Diabetes Control and Complication Trial (DCCT; 1995) –
(5y) intensive management reduces neuropathy by 64%
 Benefit persisted for 8 years .

29. BRAIN
Pharmacologic Agents
Affect Pain Differently
Descending Modulation
Central Sensitization
PNS
Local Anesthetics
Anticonvulsants
Opioids
Anticonvulsants
Opioids
NMDA-Receptor Antagonists
Tricyclic/SNRI Antidepressants
Anticonvulsants
Opioids
Tricyclic/SNRI Antidepressants
CNS
Spinal
Cord
Peripheral
Sensitization
Dorsal
Horn

31.  USP DI Volume I: Drug Information for the Healthcare Professional. 27th ed. Greenwood Village, CO:
Thomson Micromedex; 2007.

33. Tricyclic antidepressants
 Advantages
 Well documented efficacy in treatment of DPN.
 Recommended as first-line agents for all neuropathic pain
 Disadvantages
Unacceptable side effects like
 Anticholinergic effects: Dry mouth, constipation, blurred vision, urinary
retention, dizziness, tachycardia, memory impairment
 Sedation
 Alpha-1-adrenergic effects: Orthostatic hypotension / syncope
 Cardiac conduction delays/heart block: Arrhythmias, Q-T prolongation
 Other side effects: Weight gain, excessive perspiration, sexual
dysfunction

34. Duloxetine (SNRI)
Pharmacokinetics:
• Preferred in elderly patients and those with cardiac disease
• Use cautiously in patients with any hepatic insufficiency & in
renally impaired patients. (should be initiated at a lower dose &
then increased gradually.)

35. Antidepressants.
 Amitriptyline, venlafaxine, and duloxetine should be considered for the
treatment of PDN (Level B). Data are insufficient to recommend one of
these agents over the others.
 Venlafaxine may be added to gabapentin for a better response (Level C).
 There is insufficient evidence to support or refute the use of desipramine,
imipramine, fluoxetine, or the combination of nortriptyline and fluphenazine
in the treatment of PDN (Level U).
Evidence-based
guideline: Treatment of
painful diabetic
neuropathy

37. Gabapentin
 Gabapentin, alpha -2-delta subunit voltage-gated calcium-
channel antagonist --reduces excitatory neurotransmitter
release from hyperexcited neurons (e.g. glutamate,
Substance P)
 Dose titration required to achieve optimal level
 Optimal dosage 1800mg/day in PDN

38. Analog of GABA, binds to alpha 2 delta subunit of voltage
gated calcium channels.
Pregabalin

39. Pregabalin better than Gabapentin….
Feature Pregabalin Gabapentin
Tmax 1 h., Pregebalin SR (3-4 hr) 3.5 h.
Absorption Fast Slow
Oral Bioavailability > 90 % independent of dose 35% - 57 % dependent of dose
Plasma concentrations Predictable & Linear Unpredictable & non-linear
Potency based on Plasma
conc.
2.5 times more potent -
Drug-Drug interactions No Known drug-drug interactions
Oral antacids reduce
bioavailability by 20 – 30 %
Dosage (starting dose)
2 times a day (75 to 150 mg/day),
Pregebalin SR (150, 300 mg / day)
3 times a day (300 to 900
mg/day)
Overall Pharmacokinetic More stable Less stable
At high dosage Fast absorption Less absorption
Onset of action 1 – 2 days ≥ 9 days
Dose increases Non – linear Linear and predictable
Protein binding Varied Predictable levels

40. Comparative Adverse Event Profile
Adverse Events* Pregabalin Gabapentin
Dizziness 10.7 17.1%
Somnolence 8.3 19.3%
Peripheral
Edema
0.6 1.7%
Ataxia 7.1 12.5%
Weight Gain 1.2 2.9%
*Gabapentin & Pregabalin Product Monograph

41. Evidence-based guideline: Treatment
of
painful diabetic neuropathy
Anticonvulsants
 If clinically appropriate, pregabalin should be offered for the treatment of PDN
(Level A).
 Gabapentin and sodium valproate should be considered for the treatment of PDN
(Level B).
 There is insufficient evidence to support or refute the use of topiramate for the
treatment of PDN (Level U).
 Oxcarbazepine, lamotrigine, and lacosamide should probably not be considered
for the treatment of PDN (Level B).
Valproate may is potentially teratogenic, be avoided in women of childbearing age. Due to weight gain and
potential worsening of glycemic control, this drug is unlikely to be the first treatment choice for PDN.

43. Opioid
 Opioids act at two sites:
 They reduce pain signal
transmission by activating pre-
synaptic opioid receptors. This
leads to reduced intracellular
cAMP concentration, decreased
calcium ion influx and thus
inhibits the release of
excitatory neurotransmitters
(glutamate, substance P).
 At the post-synaptic level,
opioid-receptor binding evokes
a hyperpolarisation of the
neuronal membrane which
decreases probabilty of the
generation of an action
potential

44.  Weak opioids
(e.g. tramadol,
codeine)
 Strong opioids
(e.g. morphine,
oxycodone,
fentanyl)
 Dextromethorp
han(Uncompetiti
ve NMDA
receptor
antagonist

45. Distinguishing Dependence,
Tolerance, and Addiction
Physical dependence: withdrawal syndrome arises
if drug discontinued, dose substantially reduced,
or antagonist administered
Tolerance: greater amount of drug needed to
maintain therapeutic effect, or loss of effect over
time
 Addiction (psychological dependence):
psychiatric disorder characterized by continued
compulsive use of substance despite harm

46. Opioids.
 Dextromethorphan, morphine sulfate, tramadol, an oxycodone
should be considered for the treatment of PDN (Level B). Data
are insufficient to recommend one agent over the other
 The use of opioids for chronic nonmalignant pain has gained credence
over the last. Both tramadol and dextromethorphan were associated with
substantial adverse events (e.g., sedation, nausea, and constipation).
 The use of opioids can be associated with the development of novel pain
syndromes such as rebound headache.
 Chronic use of opioids leads to tolerance and frequent escalation of dose.
Evidence-based guideline: Treatment
of
painful diabetic neuropathy

47. Topical and physical treatment
Topical nitrate-Vasodilation due to nitric oxide, a derivative of glyceryl-
trinitrate, may explain its analgesic effects, while stimulation of
angiogenesis in the blood vessels supplying the nerves could explain the
temporal increase in the analgesic effects
Capsaicin
 Alkaloid, in red pepper, depletes substance P and reduces chemically
induced pain.
 Several controlled studies combined in meta-analyses seem to provide
some evidence of efficacy in diabetic neuropathic pain
 Only recommended for up to 8 weeks of treatment
 Useful in localized discomfort.

48. Other pharmacologic agents.
 Capsaicin and isosorbide dinitrate spray should be considered for the treatment
of PDN (Level B).
 Clonidine, pentoxifylline, and mexiletine should probably not be considered for
the treatment of PDN (Level B).
 The Lidocaine patch may be considered for the treatment of PDN (Level C).
 There is insufficient evidence to support or refute the usefulness of vitamins and
-lipoic acid in the treatment of PDN (Level U).
Although capsaicin has been effective in reducing pain in PDN clinical trials, many
patients are intolerant of the side effects, mainly burning pain on contact with
warm/hot water or in hot weather.
Evidence-based guideline: Treatment
of
painful diabetic neuropathy

49. Nonpharmacologic
modalities ? Percutaneous electrical nerve stimulation should be considered for
the treatment of PDN (Level B).
 Electromagnetic field treatment, low-intensity laser treatment, and
Reiki therapy should probably not be considered for the treatment of
PDN (Level B).
 Evidence is insufficient to support or refute the use of amitriptyline
plus electrotherapy for treatment of PDN (Level U).

50. Summary of recommendations
V. Bril, J. England, G.M. Franklin, et al. Evidence-based guideline: Treatment of painful diabeticneuropathy : Report of
the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine,
and the American Academy of Physical Medicine and Rehabilitation .Neurology 76 May 17, 2011

51. Future direction…
 Xenon402, a novel Nav1.7 sodium channel blocker:
 found to be effective in erythromelalgia.
 Small molecule angiotensin II type 2 receptor
(AT2R) antagonists
 EMA401
 α-Conotoxins selective for GABA(B) receptor
dependent inhibition of N-type Ca(2+) channels]
 ziconotide(Z160)

52. DIABETIC NEUROPATHY MANAGEMENT
- ALGORITHM
• Improve metabolic
control
• Explanation,
empathy
• Set realistic targets
Confirm dx
&exclude
non diabetic
etiologies
Max tolerated
therapy
Pain Clinic referral or
admission
Lignocaine infusion
Acupuncture
Add Tramadol if
breakthrough pain
Add Tramadol if breakthrough
pain
Still symptoms
Pregabalin
Duloxetine
GTN Spray
Lignocaine
Patches
Consider referral
to Acupuncture
Add Gabapentin
No response
Add Amitriptyline
10mg & titrate
Persistent pain after max tolerated dose
Try Pregabalin
Try GTN Spray
Lignocaine PatchesTry Pregabalin
Try GTN Spray
Lignocaine Patches
Gabapentin 100-
300mg od increasing
as necessary
Topical Rx
Capsaicin
Acute onset
Age <80 yrs
Insidious onset
Age >80 yrs
Amitriptyline 10mg
Titrate dose
Max 100mg od
Gabapentin
300mg bd-2 days
300mg tds – 2 days
CT 600mg tds
SE

53. Factors to consider in choosing First –Tier Agents
Factor Recommended Avoid
Medical co morbidities
Glaucoma
Orthostatic phenomena
Cardiac or
electrocardiographic
abnormality
Hypertension
Renal insufficiency
Hepatic insufficiency
Falls and balance issues
Any other first tier agent
Any other first tier agent
Any other first tier agent
Any other first tier agent
Any other first tier agent
Any other first tier agent
Any other first tier agent
TCA s
TCA s
TCA s
TCA s
Duloxetine
Pregabalin,TCAs

54. Factors to consider in choosing first tier agents
Factor Recommended Avoid
Psychiatric
comorbidities
Depression
Anxiety
Suicidal ideation
Somatic issues
sleep
Other factors
Cost
Weight gain
Edema
Duloxetine,TCAs
Any other first tier agent
Duloxetine,Pregabalin
Any first tier agent
TCA s oxycodoneCR
Duloxetine,
oxycodoneCR
Any other first tier agent
oxycodoneCR
pregabalin
TCAs , oxycodone CR
Duloxetine,Pregabalin
TCAs,Pregabalin
Pregabalin

55. Adverse effect…

56. Conclusion…
 Neuropathy is a multifactorial problem.
 Neuropathy - The most common complication and greatest source of
morbidity and mortality in diabetes patients.
 Despite advances in the understanding of the metabolic causes of
neuropathy, treatments have been limited by side effects and lack of
efficacy.
 The unmet needs of PDN has to be addressed and needs to be
managed with either the new convincing formulations of existing
molecules or with the newer agents to have a control.

59. Is it ‘‘diabetic neuropathy’’ or
‘‘neuropathy in a diabetic patient’’?
Think if-
 Rapidly progressive
 Prominent motor abnormality.
 Asymmetrical
 Motor>sensory
 Large>small fiber involvement
 Monoclonal gammopathy in serum
 CSF protein>100 gm/dl
 Elevated ESR,+ RF or ANA
 F/H/O neuropathy